4B8C | pdb_00004b8c

nuclease module of the yeast Ccr4-Not complex

External Resource: Annotation

Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
A	SCOP2B Superfamily	Ribonuclease H-like	8041933	3000143	SCOP2B (2022-06-29)
C	SCOP2B Superfamily	Ribonuclease H-like	8041933	3000143	SCOP2B (2022-06-29)
E	SCOP2B Superfamily	Ribonuclease H-like	8041933	3000143	SCOP2B (2022-06-29)
F	SCOP2B Superfamily	Ribonuclease H-like	8041933	3000143	SCOP2B (2022-06-29)
H	SCOP2B Superfamily	ARM repeat-like	8053826	3000116	SCOP2B (2022-06-29)
I	SCOP2B Superfamily	ARM repeat-like	8053826	3000116	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	ARM repeat-like	8053826	3000116	SCOP2B (2022-06-29)
G	SCOP2B Superfamily	ARM repeat-like	8053826	3000116	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	CAF1	e4b8cA1	A: mixed a+b and a/b	X: Ribonuclease H-like	H: Ribonuclease H-like (From Topology)	T: Ribonuclease H-like	F: CAF1	ECOD (1.6)
C	CAF1	e4b8cC1	A: mixed a+b and a/b	X: Ribonuclease H-like	H: Ribonuclease H-like (From Topology)	T: Ribonuclease H-like	F: CAF1	ECOD (1.6)
E	CAF1	e4b8cE1	A: mixed a+b and a/b	X: Ribonuclease H-like	H: Ribonuclease H-like (From Topology)	T: Ribonuclease H-like	F: CAF1	ECOD (1.6)
F	CAF1	e4b8cF1	A: mixed a+b and a/b	X: Ribonuclease H-like	H: Ribonuclease H-like (From Topology)	T: Ribonuclease H-like	F: CAF1	ECOD (1.6)
H	CNOT1_CAF1_bind	e4b8cH2	A: alpha superhelices	X: Repetitive alpha hairpins	H: ARM repeat (From Topology)	T: ARM repeat	F: CNOT1_CAF1_bind	ECOD (1.6)
I	CNOT1_CAF1_bind	e4b8cI2	A: alpha superhelices	X: Repetitive alpha hairpins	H: ARM repeat (From Topology)	T: ARM repeat	F: CNOT1_CAF1_bind	ECOD (1.6)
B	CNOT1_CAF1_bind	e4b8cB1	A: alpha superhelices	X: Repetitive alpha hairpins	H: ARM repeat (From Topology)	T: ARM repeat	F: CNOT1_CAF1_bind	ECOD (1.6)
G	CNOT1_CAF1_bind	e4b8cG2	A: alpha superhelices	X: Repetitive alpha hairpins	H: ARM repeat (From Topology)	T: ARM repeat	F: CNOT1_CAF1_bind	ECOD (1.6)
D	LRR_8_3	e4b8cD1	A: beta duplicates or obligate multimers	X: Single-stranded right-handed beta-helix	H: Leucine-rich repeats (From Topology)	T: Leucine-rich repeats	F: LRR_8_3	ECOD (1.6)
D	Exo_endo_phos	e4b8cD2	A: a+b four layers	X: Carbon-nitrogen hydrolase-like	H: DNase I-like (From Topology)	T: DNase I-like	F: Exo_endo_phos	ECOD (1.6)
J	LRR_8_1	e4b8cJ2	A: beta duplicates or obligate multimers	X: Single-stranded right-handed beta-helix	H: Leucine-rich repeats (From Topology)	T: Leucine-rich repeats	F: LRR_8_1	ECOD (1.6)
K	LRR_8_3	e4b8cK1	A: beta duplicates or obligate multimers	X: Single-stranded right-handed beta-helix	H: Leucine-rich repeats (From Topology)	T: Leucine-rich repeats	F: LRR_8_3	ECOD (1.6)
L	LRR_8_1	e4b8cL1	A: beta duplicates or obligate multimers	X: Single-stranded right-handed beta-helix	H: Leucine-rich repeats (From Topology)	T: Leucine-rich repeats	F: LRR_8_1	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	3.30.420.10	Alpha Beta	2-Layer Sandwich	Nucleotidyltransferase	domain 5	CATH (4.3.0)
C	3.30.420.10	Alpha Beta	2-Layer Sandwich	Nucleotidyltransferase	domain 5	CATH (4.3.0)
E	3.30.420.10	Alpha Beta	2-Layer Sandwich	Nucleotidyltransferase	domain 5	CATH (4.3.0)
F	3.30.420.10	Alpha Beta	2-Layer Sandwich	Nucleotidyltransferase	domain 5	CATH (4.3.0)
H	1.25.40.180	Mainly Alpha	Alpha Horseshoe	Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat		CATH (4.3.0)
I	1.25.40.180	Mainly Alpha	Alpha Horseshoe	Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat		CATH (4.3.0)
B	1.25.40.180	Mainly Alpha	Alpha Horseshoe	Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat		CATH (4.3.0)
G	1.25.40.180	Mainly Alpha	Alpha Horseshoe	Serine Threonine Protein Phosphatase 5, Tetratricopeptide repeat		CATH (4.3.0)
D	3.80.10.10	Alpha Beta	Alpha-Beta Horseshoe	Leucine-rich repeat, LRR (right-handed beta-alpha superhelix)	Ribonuclease Inhibitor	CATH (4.3.0)
D	3.30.1370.190	Alpha Beta	2-Layer Sandwich	Ribosomal Protein S8	Chain: A, domain 1	CATH (4.3.0)
D	4.10.60.20	Few Secondary Structures	Irregular	HIV-1 Nucleocapsid Protein		CATH (4.3.0)
J	3.80.10.10	Alpha Beta	Alpha-Beta Horseshoe	Leucine-rich repeat, LRR (right-handed beta-alpha superhelix)	Ribonuclease Inhibitor	CATH (4.3.0)
K	3.80.10.10	Alpha Beta	Alpha-Beta Horseshoe	Leucine-rich repeat, LRR (right-handed beta-alpha superhelix)	Ribonuclease Inhibitor	CATH (4.3.0)
K	3.30.1370.190	Alpha Beta	2-Layer Sandwich	Ribosomal Protein S8	Chain: A, domain 1	CATH (4.3.0)
K	4.10.60.20	Few Secondary Structures	Irregular	HIV-1 Nucleocapsid Protein		CATH (4.3.0)
L	3.80.10.10	Alpha Beta	Alpha-Beta Horseshoe	Leucine-rich repeat, LRR (right-handed beta-alpha superhelix)	Ribonuclease Inhibitor	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, C, E, F	PF04857	CAF1 family ribonuclease (CAF1)	CAF1 family ribonuclease	-	Family
B, G, H, I	PF16415	CCR4-NOT transcription complex subunit 1 CAF1-binding domain (CNOT1_CAF1_bind)	CCR4-NOT transcription complex subunit 1 CAF1-binding domain	-	Repeat
D, J, K, L	PF13855	Leucine rich repeat (LRR_8)	Leucine rich repeat	-	Repeat

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, C, E, F	POLY(A) RIBONUCLEASE POP2	3'-5'-RNA exonuclease activity catalytic activity, acting on RNA RNA exonuclease activity, producing 5'-phosphomonoesters catalytic activity, acting on a nucleic acid 3'-5' exonuclease activity RNA exonuclease activity RNA nuclease activity hydrolase activity poly(A)-specific ribonuclease activity nuclease activity hydrolase activity, acting on ester bonds exonuclease activity catalytic activity RNA binding 3'-5'-RNA exonuclease activity catalytic activity, acting on RNA RNA exonuclease activity, producing 5'-phosphomonoesters catalytic activity, acting on a nucleic acid 3'-5' exonuclease activity RNA exonuclease activity RNA nuclease activity hydrolase activity poly(A)-specific ribonuclease activity nuclease activity hydrolase activity, acting on ester bonds exonuclease activity catalytic activity RNA binding binding nucleic acid binding cation binding ion binding metal ion binding small molecule binding	regulation of cellular process negative regulation of biological process regulation of primary metabolic process nucleobase-containing compound metabolic process positive regulation of metabolic process post-transcriptional regulation of gene expression regulation of RNA metabolic process positive regulation of macromolecule metabolic process regulation of nucleobase-containing compound metabolic process regulation of biological quality RNA catabolic process mRNA catabolic process regulation of biological process positive regulation of nucleobase-containing compound metabolic process regulation of cellular process negative regulation of biological process regulation of primary metabolic process nucleobase-containing compound metabolic process positive regulation of metabolic process post-transcriptional regulation of gene expression regulation of RNA metabolic process positive regulation of macromolecule metabolic process regulation of nucleobase-containing compound metabolic process regulation of biological quality RNA catabolic process mRNA catabolic process regulation of biological process positive regulation of nucleobase-containing compound metabolic process negative regulation of metabolic process positive regulation of mRNA metabolic process primary metabolic process nucleobase-containing compound catabolic process nuclear-transcribed mRNA poly(A) tail shortening positive regulation of RNA metabolic process regulation of gene expression negative regulation of gene expression biosynthetic process negative regulation of macromolecule biosynthetic process nucleic acid catabolic process regulation of macromolecule biosynthetic process metabolic process macromolecule metabolic process regulation of metabolic process nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay catabolic process positive regulation of biological process RNA metabolic process macromolecule catabolic process mRNA destabilization regulation of mRNA catabolic process negative regulation of cellular process positive regulation of cellular process negative regulation of macromolecule metabolic process regulation of biosynthetic process nuclear-transcribed mRNA catabolic process RNA destabilization biological regulation regulation of macromolecule metabolic process regulation of catabolic process gene expression macromolecule biosynthetic process mRNA metabolic process nucleic acid metabolic process positive regulation of catabolic process regulation of mRNA stability negative regulation of biosynthetic process positive regulation of mRNA catabolic process regulation of RNA stability cellular process regulation of mRNA metabolic process transcription elongation by RNA polymerase II nucleobase-containing compound biosynthetic process RNA biosynthetic process DNA-templated transcription nucleic acid biosynthetic process DNA-templated transcription elongation transcription by RNA polymerase II positive regulation of DNA-templated transcription positive regulation of transcription elongation by RNA polymerase II positive regulation of macromolecule biosynthetic process positive regulation of biosynthetic process positive regulation of DNA-templated transcription, elongation regulation of RNA biosynthetic process regulation of transcription by RNA polymerase II regulation of DNA-templated transcription elongation regulation of transcription elongation by RNA polymerase II positive regulation of transcription by RNA polymerase II positive regulation of RNA biosynthetic process regulation of DNA-templated transcription	cell projection cellular anatomical structure mating projection cell tip mating projection tip cell pole plasma membrane bounded cell projection site of polarized growth intracellular anatomical structure cytoplasmic ribonucleoprotein granule intracellular membraneless organelle ribonucleoprotein granule intracellular organelle organelle cell projection cellular anatomical structure mating projection cell tip mating projection tip cell pole plasma membrane bounded cell projection site of polarized growth intracellular anatomical structure cytoplasmic ribonucleoprotein granule intracellular membraneless organelle ribonucleoprotein granule intracellular organelle organelle membraneless organelle cytoplasm supramolecular complex P-body protein-containing complex CCR4-NOT complex CCR4-NOT core complex intracellular protein-containing complex membrane-bounded organelle nucleus intracellular membrane-bounded organelle
B, G, H, I	GENERAL NEGATIVE REGULATOR OF TRANSCRIPTION SUBUNIT 1	ATPase activator activity molecular function activator activity molecular function regulator activity ATPase regulator activity ATP-dependent activity molecular adaptor activity	regulation of cellular process negative regulation of biological process regulation of primary metabolic process post-transcriptional regulation of gene expression negative regulation of translation negative regulation of cellular process protein metabolic process negative regulation of protein metabolic process negative regulation of macromolecule metabolic process regulation of biosynthetic process regulation of biological process regulation of protein metabolic process negative regulation of metabolic process biological regulation regulation of cellular process negative regulation of biological process regulation of primary metabolic process post-transcriptional regulation of gene expression negative regulation of translation negative regulation of cellular process protein metabolic process negative regulation of protein metabolic process negative regulation of macromolecule metabolic process regulation of biosynthetic process regulation of biological process regulation of protein metabolic process negative regulation of metabolic process biological regulation primary metabolic process regulation of macromolecule metabolic process gene expression translation macromolecule biosynthetic process regulation of gene expression negative regulation of gene expression biosynthetic process negative regulation of biosynthetic process regulation of translation negative regulation of macromolecule biosynthetic process regulation of macromolecule biosynthetic process metabolic process cellular process macromolecule metabolic process regulation of metabolic process pseudohyphal growth growth growth of unicellular organism as a thread of attached cells filamentous growth cell growth filamentous growth of a population of unicellular organisms cellular response to stimulus sexual reproduction response to stimulus reproductive process response to pheromone conjugation with cellular fusion cellular response to pheromone response to pheromone triggering conjugation with cellular fusion cellular response to chemical stimulus response to chemical nucleobase-containing compound metabolic process positive regulation of metabolic process regulation of RNA metabolic process positive regulation of macromolecule metabolic process regulation of nucleobase-containing compound metabolic process regulation of biological quality RNA catabolic process mRNA catabolic process positive regulation of nucleobase-containing compound metabolic process positive regulation of mRNA metabolic process nucleobase-containing compound catabolic process nuclear-transcribed mRNA poly(A) tail shortening positive regulation of RNA metabolic process nucleic acid catabolic process nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay catabolic process positive regulation of biological process RNA metabolic process macromolecule catabolic process mRNA destabilization regulation of mRNA catabolic process positive regulation of cellular process nuclear-transcribed mRNA catabolic process RNA destabilization regulation of catabolic process mRNA metabolic process nucleic acid metabolic process positive regulation of catabolic process regulation of mRNA stability positive regulation of mRNA catabolic process regulation of RNA stability regulation of mRNA metabolic process transcription elongation by RNA polymerase II nucleobase-containing compound biosynthetic process RNA biosynthetic process DNA-templated transcription nucleic acid biosynthetic process DNA-templated transcription elongation transcription by RNA polymerase II regulation of RNA biosynthetic process regulation of transcription by RNA polymerase II regulation of DNA-templated transcription positive regulation of DNA-templated transcription positive regulation of transcription elongation by RNA polymerase II positive regulation of macromolecule biosynthetic process positive regulation of biosynthetic process positive regulation of DNA-templated transcription, elongation regulation of DNA-templated transcription elongation regulation of transcription elongation by RNA polymerase II positive regulation of transcription by RNA polymerase II positive regulation of RNA biosynthetic process cell cycle regulation of cell cycle regulation of cellular component organization negative regulation of cytoplasmic mRNA processing body assembly regulation of cytoplasmic mRNA processing body assembly membraneless organelle assembly negative regulation of organelle assembly cellular component biogenesis cellular component organization cellular component assembly cellular component organization or biogenesis organelle assembly negative regulation of cellular component organization P-body assembly regulation of cellular component biogenesis regulation of organelle organization organelle organization negative regulation of organelle organization regulation of organelle assembly	intracellular anatomical structure cytoplasmic ribonucleoprotein granule intracellular membraneless organelle ribonucleoprotein granule intracellular organelle cellular anatomical structure organelle membraneless organelle cytoplasm supramolecular complex P-body protein-containing complex CCR4-NOT complex CCR4-NOT core complex intracellular anatomical structure cytoplasmic ribonucleoprotein granule intracellular membraneless organelle ribonucleoprotein granule intracellular organelle cellular anatomical structure organelle membraneless organelle cytoplasm supramolecular complex P-body protein-containing complex CCR4-NOT complex CCR4-NOT core complex intracellular protein-containing complex membrane-bounded organelle nucleus intracellular membrane-bounded organelle
D, J, K, L	GLUCOSE-REPRESSIBLE ALCOHOL DEHYDROGENASE TRANSCRIPTIONAL EFFECTOR	3'-5'-RNA exonuclease activity catalytic activity, acting on RNA RNA exonuclease activity, producing 5'-phosphomonoesters catalytic activity, acting on a nucleic acid 3'-5' exonuclease activity RNA exonuclease activity RNA nuclease activity hydrolase activity poly(A)-specific ribonuclease activity nuclease activity hydrolase activity, acting on ester bonds exonuclease activity catalytic activity RNA binding 3'-5'-RNA exonuclease activity catalytic activity, acting on RNA RNA exonuclease activity, producing 5'-phosphomonoesters catalytic activity, acting on a nucleic acid 3'-5' exonuclease activity RNA exonuclease activity RNA nuclease activity hydrolase activity poly(A)-specific ribonuclease activity nuclease activity hydrolase activity, acting on ester bonds exonuclease activity catalytic activity RNA binding binding nucleic acid binding cation binding ion binding metal ion binding small molecule binding	nucleobase-containing compound metabolic process DNA replication metabolic process cellular process primary metabolic process DNA metabolic process macromolecule metabolic process nucleic acid metabolic process cellular response to stimulus regulation of cellular process regulation of cell cycle phase transition response to stimulus signaling negative regulation of biological process nucleobase-containing compound metabolic process DNA replication metabolic process cellular process primary metabolic process DNA metabolic process macromolecule metabolic process nucleic acid metabolic process cellular response to stimulus regulation of cellular process regulation of cell cycle phase transition response to stimulus signaling negative regulation of biological process negative regulation of cell cycle cell cycle phase transition intracellular signal transduction cell communication negative regulation of cellular process negative regulation of cell cycle phase transition signal transduction cell cycle DNA replication checkpoint signaling regulation of cell cycle cell cycle process regulation of biological process regulation of cell cycle process biological regulation DNA integrity checkpoint signaling negative regulation of cell cycle process cell cycle checkpoint signaling regulation of primary metabolic process positive regulation of metabolic process post-transcriptional regulation of gene expression regulation of RNA metabolic process positive regulation of macromolecule metabolic process regulation of nucleobase-containing compound metabolic process regulation of biological quality RNA catabolic process mRNA catabolic process positive regulation of nucleobase-containing compound metabolic process negative regulation of metabolic process positive regulation of mRNA metabolic process nucleobase-containing compound catabolic process nuclear-transcribed mRNA poly(A) tail shortening positive regulation of RNA metabolic process regulation of gene expression negative regulation of gene expression biosynthetic process negative regulation of macromolecule biosynthetic process nucleic acid catabolic process regulation of macromolecule biosynthetic process regulation of metabolic process nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay catabolic process positive regulation of biological process RNA metabolic process macromolecule catabolic process mRNA destabilization regulation of mRNA catabolic process positive regulation of cellular process negative regulation of macromolecule metabolic process regulation of biosynthetic process nuclear-transcribed mRNA catabolic process RNA destabilization regulation of macromolecule metabolic process regulation of catabolic process gene expression macromolecule biosynthetic process mRNA metabolic process positive regulation of catabolic process regulation of mRNA stability negative regulation of biosynthetic process positive regulation of mRNA catabolic process regulation of RNA stability regulation of mRNA metabolic process transcription elongation by RNA polymerase II nucleobase-containing compound biosynthetic process RNA biosynthetic process DNA-templated transcription nucleic acid biosynthetic process DNA-templated transcription elongation transcription by RNA polymerase II regulation of RNA biosynthetic process regulation of transcription by RNA polymerase II regulation of DNA-templated transcription positive regulation of DNA-templated transcription positive regulation of transcription elongation by RNA polymerase II positive regulation of macromolecule biosynthetic process positive regulation of biosynthetic process positive regulation of DNA-templated transcription, elongation regulation of DNA-templated transcription elongation regulation of transcription elongation by RNA polymerase II positive regulation of transcription by RNA polymerase II positive regulation of RNA biosynthetic process traversing start control point of mitotic cell cycle regulation of cell cycle G1/S phase transition cell cycle G1/S phase transition mitotic cell cycle regulation of mitotic cell cycle positive regulation of mitotic cell cycle phase transition positive regulation of cell cycle process positive regulation of mitotic cell cycle positive regulation of G1/S transition of mitotic cell cycle positive regulation of cell cycle regulation of mitotic cell cycle phase transition positive regulation of cell cycle G1/S phase transition mitotic cell cycle process regulation of G1/S transition of mitotic cell cycle positive regulation of cell cycle phase transition G1/S transition of mitotic cell cycle mitotic cell cycle phase transition	CCR4-NOT complex protein-containing complex intracellular protein-containing complex intracellular anatomical structure cytoplasmic ribonucleoprotein granule intracellular membraneless organelle ribonucleoprotein granule intracellular organelle cellular anatomical structure organelle membraneless organelle cytoplasm supramolecular complex P-body CCR4-NOT complex protein-containing complex intracellular protein-containing complex intracellular anatomical structure cytoplasmic ribonucleoprotein granule intracellular membraneless organelle ribonucleoprotein granule intracellular organelle cellular anatomical structure organelle membraneless organelle cytoplasm supramolecular complex P-body membrane-bounded organelle RNA polymerase II, holoenzyme transcription elongation factor complex nucleus membrane-enclosed lumen nuclear protein-containing complex transferase complex intracellular organelle lumen nucleoplasm catalytic complex intracellular membrane-bounded organelle Cdc73/Paf1 complex transferase complex, transferring phosphorus-containing groups nuclear DNA-directed RNA polymerase complex organelle lumen RNA polymerase complex DNA-directed RNA polymerase complex nuclear lumen CCR4-NOT core complex

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, C, E, F	IPR036397	Ribonuclease H superfamily	Homologous Superfamily
A, C, E, F	IPR039637	CCR4-NOT transcription complex subunit 7/8/Pop2	Family
A, C, E, F	IPR006941	Ribonuclease CAF1	Family
A, C, E, F	IPR012337	Ribonuclease H-like superfamily	Homologous Superfamily
B, G, H, I	IPR032193	CCR4-NOT transcription complex subunit 1, TTP binding domain	Domain
B, G, H, I	IPR032195	CCR4-NOT transcription complex subunit 1, HEAT repeat 1	Domain
B, G, H, I	IPR038535	CCR4-NOT subunit 1, TTP binding domain superfamily	Homologous Superfamily
B, G, H, I	IPR040398	CCR4-NOT transcription complex subunit 1	Family
B, G, H, I	IPR024557	CCR4-NOT transcription complex subunit 1, domain 4	Domain
B, G, H, I	IPR007196	CCR4-Not complex component, Not1, C-terminal	Domain
B, G, H, I	IPR032194	CCR4-NOT transcription complex subunit 1, HEAT repeat	Domain
B, G, H, I	IPR032191	CCR4-NOT transcription complex subunit 1, CAF1-binding domain	Domain
D, J, K, L	IPR005135	Endonuclease/exonuclease/phosphatase	Domain
D, J, K, L	IPR050410	CCR4/nocturin mRNA turnover and transcription	Family
D, J, K, L	IPR001611	Leucine-rich repeat	Repeat
D, J, K, L	IPR003591	Leucine-rich repeat, typical subtype	Repeat
D, J, K, L	IPR032675	Leucine-rich repeat domain superfamily	Homologous Superfamily
D, J, K, L	IPR036691	Endonuclease/exonuclease/phosphatase superfamily	Homologous Superfamily

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.